Data from Gene–Environment Analyses Reveal Novel Genetic Candidates with Prenatal Tobacco Exposure in Relation to Risk for Childhood Acute Lymphoblastic Leukemia

Abstract

<div>AbstractBackground:<p>Associations between maternal tobacco exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL) have yielded mixed results. This may be due to biases in self-reported smoking or other differences in individual-level risk factors. We utilized a biological marker of maternal tobacco exposure to evaluate the association between maternal tobacco exposure during pregnancy, genetics, and subsequent childhood ALL risk in two large population-based studies of childhood ALL in California.</p>Methods:<p>Maternal exposure to tobacco smoke was assessed with a validated methylation marker (cg05575921) of the aryl hydrocarbon receptor repressor (<i>AHRR</i>) gene in newborn dried blood spots. We adjusted for sex, birthweight, gestational age, mode of delivery, year of birth, <i>AHRR</i> quantitative trait locus (mQTL) rs77111113, and a polygenetic risk score for childhood ALL. We additionally adjusted for principal components in a gene–environment interaction testing method that incorporates gene-only and environment-only effects along with interactions.</p>Results:<p><i>AHRR</i> hypomethylation overall was not associated with childhood ALL. In gene–environment interaction testing, several genetic variants displayed significant interaction with <i>AHRR</i> hypomethylation and childhood ALL.</p>Conclusions:<p>Our results suggest that novel candidates in <i>PTPRK</i> and <i>DPP6</i> may play a role in tobacco-related leukemogenesis. Further research is necessary to better understand the effects of tobacco and these variants on childhood ALL risk.</p>Impact:<p>Despite the lack of an overall “main effect,” tobacco exposure during pregnancy affects childhood ALL risk depending on specific genetic variants.</p></div>